The research described is designed to test the propositions that (i) there are wide variations among women in the extrahepatic metabolism of plasma progesterone to bioactive products with diverse actions, (ii) there are multiple premenstrual syndromes (PMS), and (iii) premenstrual disabilities are caused by the actions of progesterone and its bioactive metabolites. Progesterone (P), during the mid-luteal phase of the ovarian cycles of women, is produced in massive amounts, viz., 40-50 mg/24 h. The known bioactive metabolites of plasma P include: (i) a mineralocorticosteroid, viz., deoxycorticosterone (DOC), which is produced by 21-hydroxylation of plasma P in extrahepatic, extraadrenal tissues, and (ii) the 3alpha/beta-reduced-5alpha-pregnanolones, which act by way of P receptor-independent, nongenomic mechanisms via the GABA/A (gamma-aminobutyric acid) receptor-chloride channel complex to modulate the neuroinhibitory action of GABA. We have established that the transfer constant of conversion of plasma P to DOC, [p]P-DOC, varies widely (by 30-fold) among normal persons, thus accounting for the great variation in the rate of DOC formation among ovulatory women during the luteal phase of the ovarian cycle. From recent findings, we estimate that 50% of plasma P clearance is accounted for by metabolism in extrahepatic tissues and that 80-90% of this extrahepatic P metabolism proceeds initially by 5alpha-reduction to give 5alpha-dihydro- progesterone (5alpha-DHP). In turn, 70% of plasma 5alpha-DHP clearance occurs in extrahepatic sites to give 3alpha/beta-reduced-5alpha- pregnanolones, which are bioactive in selected tissues, notably brain. We also find that the extrahepatic inactivation of the bioactive 5alpha- pregnanolones is accomplished by peculiar 5alpha-pregnanolone-6alpha- hydroxylase enzymes that are widely distributed, but exclusively in extrahepatic tissues and are notably high in brain, breast, and skin. Importantly, we also find that the extrahepatic metabolism of 5alpha-DHP, like [p]P,DOC, varies widely among women. We propose to test the hypothesis that various patterns of extrahepatic P metabolism to bioactive metabolites are correlated with the recurrence of premenstrual symptoms of varying severity that may result in multiple symptom clusters. The goals of the research presented are (i) to define the factors, which are independent of genetic variation, that may regulate P/5alpha-DHP metabolism in women; (ii) to establish the nature and cause(s) of inherent differences among ovulatory women in P/5alpha-DHP metabolism; (iii) to investigate and compare the in vivo metabolism of P/5alpha-DHP in 30 asymptomatic women, 5 of whom are obese, with that in 25 women with severe PMS, i.e., the late luteal phase dysphoric disorder (LLPDD); and (iv) compare the pattern of in vivo metabolism of P/5alpha- DHP in these women with the specific activities of P/5alpha-DHP metabolizing enzymes in skin fibroblasts of the same woman. We predict that there is polymorphism of the genes that encode the extrahepatic enzymes that metabolize P/5alpha-DHP and that differences in enzyme activities resulting therefrom cause variations in the rate(s) of formation of bioactive metabolites of P and, thereby, the symptoms of PMS. The cause of these person-to-person variations in P/5alpha-DHP metabolism can be identified by the in vivo and in vitro studies proposed.